SABCS 2011 Report – Progress in the management of HER2-positive breast cancer

by Dr Sunil Upadhyay – Patients with HER2-positive tumours are known to carry a poor prognosis. The standard recommendation is that the majority of newly diagnosed patients with HER2-positive tumours should receive adjuvant chemotherapy and trastuzumab preferably for one year. There is emerging evidence that patients with even smaller lesions (<20mm) benefit from adjuvant trastuzumab though it is also accepted that HER2-positive tumours are heterogeneous in their behaviour. In the absence of adjuvant trastuzumab, the majority of these patients not only carry a persistent, long-term risk of relapse but also death. Unfortunately, some of these patients may not have received adjuvant trastuzumab due to a variety of reasons. Patients in the control arm of the HERA trial were offered and many received trastuzumab at a later stage but there is no prospective controlled trial to show the outcome of anti-HER2 therapy in patients after a 2-3 year interval from the initial diagnosis.

Lapatinib an oral reversible inhibitor of EGFR and HER2 receptor tyrosine kinases is approved for the treatment of metastatic HER2-positive tumours in trastuzumab pre-treated patients in combination with capecitabine and trastuzumab naïve disease with letrozole. At the SABCS 2011, Paul Goss presented the results from the TEACH trial which looked at the role of lapatinib in women with early stage HER2-positive breast cancer who did not get anti-HER2 therapy in the adjuvant setting (n=3147) along with their standard systemic therapies. In this study, 3161 patients, with the median time since initial diagnosis of 2.7 months, who completed neoadjuvant/adjuvant chemotherapy without anti-HER2 therapy for HER2-positive stage I-IIIc breast cancer and had no evidence of recurrence were randomised 1:1 to oral lapatinib 1500mg daily (n=1571) or placebo (1576) for one year. The primary endpoint was DFS and the secondary endpoints were overall survival, recurrence free survival, CNS recurrence rate, toxicity and QoL.  At a median follow-up of 4 years, a 17% reduction in risk of disease recurrence was observed with lapatinib compared to placebo (HR 0.83, p=0.053), which did not attain statistical significance in the intention to treat population. However, a significant benefit in favour of lapatinib was observed in patients with hormone receptor negative tumours (HR 0.68) and in patients randomised within one year of diagnosis (HR 0.70). The incidence of CNS relapse was either delayed or smaller in number compared to the placebo arm (HR 0.65). As expected, adverse events like diarrhoea and rash were more common with lapatinib but no treatment-related deaths were observed in this trial.

TEACH trial design is unique because it is simply the exploitation of the window of opportunity where patients with HER2-positive tumours who did not get adjuvant trastuzumab could be identified and recruited. Nowadays patients with the smallest HER2-positive tumours are frequently treated with adjuvant trastuzumab, at least in the developed world. Therefore, it is going to be extremely hard to find these types of patients. Moreover, since the majority of the HER2-positive patients, who have not received adjuvant trastuzumab, if they are going to relapse, will relapse within three years, one can assume that the patients recruited in this study were relatively of better prognostic type, particularly since 50% of the cases had ER negative disease in this trial.

The ALTO trial data is public knowledge. lapatinib-alone patients (arm 2) were found to have an inferior outcome compared to trastuzumab alone or the combination group of patients. Therefore, together with ALTO, TEACH data provides the evidence that lapatinib alone is not going to be used in an adjuvant setting and its main role remains confined to the metastatic setting. However, the combination of trastuzumab with lapatinib may turn out to be a superior choice. Abstract S 4-7

A poster presentation by Denis Yardley (Abstract P1-12-10) on the use of lapatinib in combination with nab-paclitaxel in metastatic breast cancer (n=60) showed an overall response rate of 53% with a median PFS of 39.7 weeks and only a 5% rate of diarrhoea. However, there is evidence from the Memorial Sloan Kettering Hospital that a combination of lapatinib with trastuzumab plus paclitaxel is better, at a cost of higher toxicity hence the need for dose reduction to reduce toxicity. Therefore, these results support the view that lapatinib has an important role to play in combination with other molecular agents with or without chemotherapy along with other newer agents in the management of HER2-positive breast cancer patients.